esc b-adrenergic receptor blockers 2004

8/19/2019 ESC B-Adrenergic Receptor Blockers 2004

1/22

ESC Expert consensus document

Expert consensus document on b-adrenergic

receptor blockers

The Task Force on Beta-Blockers of the European Societyof Cardiology

Task Force Members, Jose Lopez-Sendon, Chairperson* (Spain), Karl Swedberg(Sweden), John McMurray (UK), Juan Tamargo (Spain), Aldo P. Maggioni (Italy),Henry Dargie (UK), Michal Tendera (Poland), Finn Waagstein (Sweden), Jan Kjekshus

(Norway), Philippe Lechat (France), Christian Torp-Pedersen (Denmark)

ESCCommittee forPractice Guidelines (CPG), Silvia G. Priori (Chairperson) (Italy),Maria AngelesAlonso Garcıa (Spain),

Jean-Jacques Blanc (France), Andrzej Budaj (Poland), Martin Cowie (UK), Veronica Dean (France), Jaap Deckers

(The Netherlands), Enrique Fernandez Burgos (Spain), John Lekakis (Greece), Bertil Lindahl (Sweden), Gianfranco

Mazzotta (Italy), Keith McGregor (France), Jo~ao Morais (Portugal), Ali Oto (Turkey), Otto A. Smiseth (Norway)

Document Reviewers, Maria Angeles Alonso Garcıa (CPG Review Coordinator) (Spain); Diego Ardissino (Italy),

Cristina Avendano (Spain), Carina Blomstr€om-Lundqvist (Sweden), Denis Clement (Belgium), Helmut Drexler

(Germany), Roberto Ferrari (Italy), Keith A. Fox (UK), Desmond Julian (UK), Peter Kearney (Ireland), Werner Klein

(Austria), Lars K €ober (Denmark), Giuseppe Mancia (Italy), Markku Nieminen (Finland), Witold Ruzyllo (Poland),

Maarten Simoons (The Netherlands), Kristian Thygesen (Denmark), Gianni Tognoni (Italy), Isabella Tritto (Italy),

Lars Wallentin (Sweden)

Table of contents

Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . 1342Classes of recommendations . . . . . . . . . . . . . . 1342Levels of evidence. . . . . . . . . . . . . . . . . . . . . 1342Introduction. . . . . . . . . . . . . . . . . . . . . . . . . 1342Pharmacology. . . . . . . . . . . . . . . . . . . . . . . . 1343

Definition . . . . . . . . . . . . . . . . . . . . . . . . 1343Classification of b-blockers . . . . . . . . . . . . . 1343Pharmacokinetic properties . . . . . . . . . . . . . 1343

Lipophilic drugs. . . . . . . . . . . . . . . . . . . 1344Hydrophilic drugs. . . . . . . . . . . . . . . . . . 1344

Balanced clearance drugs . . . . . . . . . . . . 1344Mechanism of action . . . . . . . . . . . . . . . . . 1344Adverse events . . . . . . . . . . . . . . . . . . . . . 1345

Cardiovascular . . . . . . . . . . . . . . . . . . . 1345Metabolic . . . . . . . . . . . . . . . . . . . . . . 1345Pulmonary . . . . . . . . . . . . . . . . . . . . . . 1345

Central effects . . . . . . . . . . . . . . . . . . . 1345Sexual dysfunction . . . . . . . . . . . . . . . . . 1345

Contraindications . . . . . . . . . . . . . . . . . . . 1345Drug interactions . . . . . . . . . . . . . . . . . . . 1345Dosing of b-blockers . . . . . . . . . . . . . . . . . 1346

Clinical efficacy and use . . . . . . . . . . . . . . . . . 1346Acute myocardial infarction (AMI) . . . . . . . . . 1346Secondary prevention after

myocardial infarction . . . . . . . . . . . . . . . 1347Non-ST-segment elevation acute coronary

syndromes . . . . . . . . . . . . . . . . . . . . . . 1348Chronic, stable ischaemic heart disease . . . . . 1348Heart failure . . . . . . . . . . . . . . . . . . . . . . 1349

Heart failure and preserved systolic function 1351Acute heart failure . . . . . . . . . . . . . . . . 1351

Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . 1352Sinus tachycardia. . . . . . . . . . . . . . . . . . 1352Supraventricular tachycardias. . . . . . . . . . 1352Tachycardias in WPW syndrome . . . . . . . . 1353Atrial flutter. . . . . . . . . . . . . . . . . . . . . 1353Atrial fibrillation . . . . . . . . . . . . . . . . . . 1353Ventricular arrhythmias . . . . . . . . . . . . . 1353

Prevention of sudden cardiac death. . . . . . . . 1353Acute myocardial infarction. . . . . . . . . . . 1354

* Corresponding author. Chairperson: Jose Lopez-Sendon, Cardiology,Area 1200, Hospital Universitario Gregorio Mara~non, Doctor Esquerdo 46,

28007 Madrid. Spain. Tel.: þ34-91-586-8295; fax: þ34-91-586-6672.E-mail address: [email protected] (J. Lopez-Sendon).

0195-668X/$ - see front matter c 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.doi:10.1016/j.ehj.2004.06.002

European Heart Journal (2004) 25, 1341–1362

http://mail%20to:%20mailto%[email protected]/http://mail%20to:%20mailto%[email protected]/


2/22

Preamble

Guidelines and Expert Consensus documents aim topresent all the relevant evidence on a particular issue inorder to help physicians to weigh the benefits and risksof a particular diagnostic or therapeutic procedure.They should be helpful in everyday clinical decision-making.

A great number of Guidelines and Expert ConsensusDocuments have been issued in recent years by the Eu-ropean Society of Cardiology (ESC) and by different or-ganisations and other related societies. This profusioncan put at stake the authority and validity of guidelines,which can only be guaranteed if they have been devel-oped by an unquestionable decision-making process. Thisis one of the reasons why the ESC and others have issued

recommendations for formulating and issuing Guidelinesand Expert Consensus Documents.

In spite of the fact that standards for issuing goodquality Guidelines and Expert Consensus Documents arewell defined, recent surveys of Guidelines and ExpertConsensus Documents published in peer-reviewed jour-nals between 1985 and 1998 have shown that methodo-logical standards were not complied with in the vastmajority of cases. It is therefore of great importance thatguidelines and recommendations are presented in formatsthat are easily interpreted. Subsequently, their imple-mentation programmes must also be well conducted.

The ESC Committee for Practice Guidelines (CPG) su-pervises and coordinates the preparation of new Guide-lines and Expert Consensus Documents produced by TaskForces, expert groups or consensus panels. The chosenexperts in these writing panels are asked to provide dis-closure statements of all relationships they may havewhich might be perceived as real or potential conflicts ofinterest. These disclosure forms are kept on file at theEuropean Heart House, headquarters of the ESC. TheCommittee is also responsible for the endorsement ofthese Guidelines and Expert Consensus Documents orstatements.

The Task Force has classified and ranked the useful-ness or efficacy of the recommended procedure and/or

treatment and the Level of Evidence as indicated in thetables below:

Classes of Recommendations

*Use of Class III is discouraged by the ESC.

Levels of Evidence

Introduction

b-Blocker therapy plays a major role in the treatment ofcardiovascular diseases. For many years b-blockers wereused for their antiischaemic, antiarryhthmic and anti-hypertensive properties. More recently, the benefit ofadrenoceptor blockade was also established in patientswith heart failure. The aim of this document is to reviewthe rationale and clinical evidence for the use of b-ad-renergic blockers in patients with cardiovascular disease.

The members for the Beta-blockers in CardiovascularDisease Task Force were nominated by the Committee forPractice Guidelines (CPG) of the European Society ofCardiology (ESC). A specific literature search was carriedout for original articles in peer review journals included inMedline. In addition, theESC as well as theAmerican HeartAssociation/American College of Cardiology guidelineswith reference to the use of b-blockers were carefullyreviewed. Most of the previously made recommendationswere maintained; some were updated and a few are newaccording to recent evidence in the literature.

Using recommendations which are graded provides asimple method for guidance. Levels of recommendationare derived from clinical trials, conducted in selectedgroups of patients that may not be representative of

Class I: Evidence and/or general agreement that agiven procedure/treatment is beneficial,

useful and effective;Class II: Conflicting evidence and/or a divergence

of opinion about the usefulness/efficacyof the procedure/treatment;

Class IIa: Weight of evidence/opinion is in favour ofusefulness/efficacy;

Class IIb: Usefulness/efficacy is less well establishedby evidence/opinion;

Class III*: Evidence or general agreement that thetreatment is not useful/effective and insome cases may be harmful.

Level of Evidence A Data derived from multiple ran-domised clinical trials or meta-analyses

Level of Evidence B Data derived from a single ran-domised clinical trial or non-randomised studies

Level of Evidence C Consensus of opinion of the ex-perts and/or small studies

Heart failure . . . . . . . . . . . . . . . . . . . . 1354Dilated cardiomyopathy . . . . . . . . . . . . . 1354Hypertrophic cardiomyopathy. . . . . . . . . . 1354Mitral valve prolapse . . . . . . . . . . . . . . . 1354Myocardial bridging . . . . . . . . . . . . . . . . 1355Long QT syndrome (LQTS) . . . . . . . . . . . . 1355Catecholaminergic polymorphic ventricular

tachycardia . . . . . . . . . . . . . . . . . . . 1355

SCD in the normal heart . . . . . . . . . . . . . 1355Other situations . . . . . . . . . . . . . . . . . . 1355

Hypertension . . . . . . . . . . . . . . . . . . . . . . 1355Aortic dissection . . . . . . . . . . . . . . . . . . . . 1356Hypertrophic cardiomyopathy . . . . . . . . . . . 1356Prophylactic use in non-cardiac surgery . . . . . 1356Vasovagal syncope. . . . . . . . . . . . . . . . . . . 1357b-Blockers during pregnancy . . . . . . . . . . . . 1357

References . . . . . . . . . . . . . . . . . . . . . . . . . 1357

1342 ESC Expert consensus document


3/22

broader populations; in fact, patients with contraindica-tions are excluded from clinical trials. Besides, the samestrength of evidence may reflect different clinical bene-fit: mortality, morbidity, clinical symptoms or combinedend-points; large or small benefit albeit statistically sig-nificant; easily obtained or only observed, or lost, afterseveral years of treatment. Finally, in individual cases therecommended therapy may only be a treatment option

and other alternatives may be equally acceptable or evenmore appropriate. An effort was made to include thisinformation in a relatively short document.

The document prepared by the task force was circu-lated among a review board appointed by the ESC andapproved by the Committee for Practice Guidelines ofthe ESC. The final document was sent to the EuropeanHeart Journal for a formal peer review.

This consensus document represents the views of theESC and was arrived at after careful consideration of theavailable evidence. Health professionals are expected totake them fully into account when exercising their clin-ical judgement. This consensus document does not,however, override the individual responsibility of healthprofessionals to make appropriate decisions in the cir-cumstances of the individual patient, in consultationwith that patient, and where appropriate and necessarythe patient’s guardian or carer.

Pharmacology

Definition

b-Adrenergic antagonists (b-blockers) bind selectively tothe b-adrenoceptors producing a competitive and re-

versible antagonism of the effects of b-adrenergic stim-uli on various organs (Table 1). Their pharmacologicaleffects can be explained from the knowledge of the re-sponses elicited by these receptors in the various tissuesand the activity of the sympathetic tone.1;2 Thus,b-blockers have relatively little effect on heart rate andcontractility in an individual at rest but slow heart rateand decrease cardiac contractility when the sympathetic

nervous system is activated, i.e., during exercise orstress.

Classification of b-blockers

b-Blockers can be broadly classified into (a)non-selective,those producing a competitive blockade of both b1- andb2-adrenergic receptors and (b) those with much higheraffinity for the b1 than for the b2 receptors usually calledb1-selective (Table 2).

1 – 4 Selectivity is, however, dose-dependent and decreases or disappears when larger dosesare used. Paradoxically, someb-blockers can exert a weakagonist response (intrinsic sympathomimetic activity

(ISA), and can stimulate and block the b-adrenoceptor.Several b-blockers have peripheral vasodilator activitymediated via a1-adrenoceptor blockade (carvedilol, la-betalol), b2-adrenergic receptor agonism (celiprolol) orvia mechanisms independent of the adrenoceptor block-ade (bucindolol, nebivolol). In addition,b-blockers can beclassified as lipophilic or hydrophilic.

Pharmacokinetic properties

There are important pharmacokinetic differences amongb-blockers1 – 4 (Table 1).

Table 1 Effects mediated by b1- and b2-adrenoceptors

Tissue Receptor Effect

HeartSA node b1, b2 Increase in heart rateAV node b1, b2 Increase in conduction velocityAtria b1, b2 Increase in contractility

Ventricles b1, b2 Increase in contractility, conduction velocity and automaticityof idioventricular pacemakers

Arteries b2 VasodilationVeins b2 VasodilationSkeletal muscle b2 Vasodilation, increased contractility

Glycogenolysis, Kþ uptake

Liver b2 Glycogenolysis and gluconeogenesisPancreas (b cells) b2 Insulin and glucagon secretionFat cells b1 LipolysisBronchi b2 BronchodilationKidney b1 Renin releaseGallbladder and ducts b2 RelaxationUrinary bladder detrusor b2 RelaxationUterus b2 RelaxationGastrointestinal b2 RelaxationNerve terminals b2 Promotes noradrenaline releaseParathyroid glands b1, b2 Parathormone secretionThyroid gland b2 T4!T3 conversion

SA: Sino-Atrial; AV: Auriculo-Ventricular.

ESC Expert consensus document 1343


4/22

Lipophilic drugs

Lipophilic drugs (metoprolol, propranolol, timolol) arerapidly and completely absorbed from the gastrointesti-nal tract but are extensively metabolised in the gut walland in the liver (first pass effect), so that their oral

bioavailability is low (10–30%). These drugs may accu-mulate in patients with reduced hepatic blood flow (i.e.,elderly, congestive heart failure, liver cirrhosis). Lipo-philic drugs present short elimination half-lives (1-5 h)and they easily enter the central nervous system (CNS),which may account for a greater incidence of centralside-effects.

Hydrophilic drugs

Hydrophilic drugs (atenolol, esmolol) are absorbed in-completely from the gastrointestinal tract and are ex-creted unchanged or as active metabolites by the kidney.They have longer half-lives (6–24 h), and do not interactwith other liver-metabolised drugs. They barely cross the

blood–brain barrier. Elimination half-life is increasedwhen glomerular filtration rate is reduced (i.e., elderly,renal insufficiency).

Balanced clearance drugs

Bisoprolol has a low first-pass metabolism, enters theCNS and is excreted in equal proportion by hepatic andrenal routes. Carvedilol has a low oral bioavailability dueto an extensive first pass effect. It binds to plasma pro-teins and is eliminated by hepatic metabolism.4 Esmololis an ultra short-acting drug. It is administered i.v. andrapidly hydrolysed by red cell esterases (half-life 9 min).5

Mechanism of action

The mechanisms of action are diverse, not yet com-pletely understood and probably with important differ-ences between agents. The prevention of the cardiotoxic

effects of catecholamines plays a central role.6 –

8 Thefollowing mechanisms are also considered: (a) Antihy-pertensive action. Associated with a decrease in cardiacoutput, inhibition of the release of renin and productionof angiotensin II, blockade of presynaptic a-adrenocep-tors that increase the release of norepinephrine fromsympathetic nerve terminals and decrease of cen-tral vasomotor activity.1 – 9 (b) Anti-ischaemic actionb-blockers decrease myocardial oxygen demand by re-ducing heart rate, cardiac contractility, and systolicblood pressure.10 In addition, prolongation of diastolecaused by a reduction in heart rate may increase myo-cardial perfusion. (c) Reduction of renin release andangiotensin II and aldosterone production by blocking ofb1-adrenoceptors on renal juxtaglomerular cells. (d)Improvement of left ventricular structure and function,decreasing ventricular size and increasing ejection frac-tion.6 – 8 b-blockers may improve cardiac function be-cause they: (i) reduce heart rate, prolong diastolic fillingand coronary diastolic perfusion time, (ii) decrease my-ocardial oxygen demands, (iii) improve myocardial en-ergetics by inhibiting catecholamine-induced releaseof free fatty acids from adipose tissue, (iv) upregulateb-adrenergic receptors and (v) reduce myocardialoxidative stress.1;11;12 (e) The antiarrhythmic effect, theresult of direct cardiac electrophysiological effects

Table 2 Pharmacological classification of commonly used b-adrenergic antagonists (b-blockers)

b-blocker ISA Lipid solubility Peripheral vasodilation i.v. Average daily oral dose

I. Non-selective ( b1 þ b2) adrenergic antagonists

Carteolol + Low 2.5–20 mg once/twice dailyNadolol 0 Low 40–320 mg once dailyPenbutolol + Moderate 20–80 mg once/twice dailyPindolol ++ High 10–40 mg twice daily

Propranolol 0 High + 40–180 mg twice dailySotalol 0 Low +Timolol 0 High 5–40 mg twice daily

II. Selective b1-adrenergic antagonists

Acebutolol + Moderate 200–800 mg once/twice dailyAtenolol 0 Low + 25–100 mg once dailyBetaxolol 0 Moderate 5–20 mg once dailyBisoprolol 0 Moderate 2.5–10 mg once dailyCeliprolol + Moderate + 200–600 mg once dailyEsmolol 0 Low + Only i.v.Metoprolol 0 High + 50–100 mg once/twice dailyNevibolol 0 + 2.5–5 mg once daily

III. a1- and b-adrenergic antagonists

Bucindolol + Moderate + 25–100 mg twice daily

Carvedilol 0 Moderate + 3.125–50 mg twice dailyLabetalol + Low + 200–800 mg twice daily

ISA: Intrinsic Sympathomimetic Activity; i.v.: Intravenous Administration possible; AMI: Acute Myocardial Infarction; CHF: Chronic Heart Failure.

Included only b-blockers with demonstrated efficacy on clinical outcomes and supporting the guidelines recommendations.* In some studies there was lack of evidence for peripheral a1-adrenoceptor blockade during long-term treatment of heart failure with carvedilol.

229



5/22

(reduced heart rate, decreased spontaneous firing ofectopic pacemakers, slowed conduction and increasedrefractory period of AV node), reduces the sympatheticdrive and myocardial ischaemia, improves baroreflexfunction and prevents catecholamine-induced hypokale-mia.13 Other mechanisms include: inhibition of cardiacapoptosis mediated via the activation of the b-adrener-gic pathway,14 inhibition of platelet aggregation,1 re-

duction of the mechanical stress imposed on the plaque,preventing plaque rupture, resensitization of the b-ad-renergic pathway and changes in myocardial gene ex-pression, i.e., an increase in sarcoplasmic reticulumcalcium ATPase, mRNA and a-myosin heavy chain mRNAand a decrease in b-myosin heavy chain mRNA levels.15

Finally, some b-blockers exhibit antioxidant propertiesand inhibit vascular smooth muscle cell proliferation.4

Adverse events

In general, b-adrenergic inhibitors are well tolerated, butserious side-effects may occur, especially when theseagents are used in large doses.1;2

Cardiovascular

b-blockers reduce heart rate, decrease the firing rate ofcardiac ectopic pacemakers and slow conduction andincrease the refractory period of the AV node. Thus, theymay cause extreme bradycardia and AV block. Theseeffects are seen mainly in patients with impaired sinusnode function and AV-node conduction and are rare whenb-blockers are given intravenously to patients with acutemyocardial infarction16 or orally in patients with chronicheart failure.17 b-blockers decrease tissue blood flow dueto blockade of vascular b2-receptors and unopposedstimulation of vascular a-adrenoceptors. As a result,

they can produce cold extremities and Raynaud’s phe-nomenon and worsen the symptoms in patients with se-vere peripheral vascular disease.4 However, the clinicalbenefits of b-adrenergic antagonists in patients withperipheral vascular disease and coronary artery diseasemay be very important.18;19 These side-effects are lesspronounced with drugs exhibiting vasodilator effects andwith selective b1 agents. b-blockers can also increase thecoronary vasomotor tone, in part because of unopposeda-adrenergic mediated vasoconstriction.

Metabolic

In patients with insulin-dependent type I diabetes non-selective b-blockers mask some of the warning symptomsof hypoglycaemia (tremor, tachycardia); the other signsof hypoglycaemia (e.g., sweating) are maintained. Aselective b-blocker should therefore be preferred atleast in insulin dependent patients. In any case, theclinical benefit of treatment with b-blockers outweighsthe risk, at least after myocardial infarction.20;21 In onestudy carvedilol decreased the new onset diabetes inpatients with heart failure.22

Pulmonary

b-blockers can lead to a life-threatening increase in air-way resistance and are contraindicated in patients with

asthma or bronchospastic chronic obstructive pulmonarydisease. In some patients with chronic obstructive pul-monary disease, the potential benefit of using b-blockersmay outweigh the risk of worsening pulmonary function.A history of asthma, however, should still be considereda contraindication to the use of any b-blocker, butchronic obstructive pulmonary disease is not a contra-indication unless there is a significant reactive airway

disease.23

Central effects

Central effects (fatigue, headache, sleep disturbances,insomnia and vivid dreams, depression) are less commonwith hydrophilic drugs.24 In some patients the fatigue maybe related to a decrease in blood flow to skeletal muscles;in other cases, it may be secondary to a central effect.

Sexual dysfunction

In some patients b-blockers may cause or aggravate im-potence and loss of libido.

Abrupt discontinuation of b-blockers after chronictreatment can lead to rebound symptoms (i.e., hyper-tension, arrhythmias, exacerbated angina).25;26 This in-creased risk is related with upregulation of b-adrenoceptors during chronic treatment.

Contraindications

The contraindications to initiate b-blocker treatmentinclude asthma, symptomatic hypotension or bradycardiaand severe decompensated heart failure (see later).Contraindications may be relative, in patients in whomthe benefit of therapy may outweigh the risk of untowardeffects. Chronic obstructive lung disease without bron-chospastic activity and peripheral vascular disease arenot considered as absolute contraindications and highrisk patients may obtain a significant benefit from thistherapy.27;28 Patients with heart failure and bradycardiadue to sick sinus node or second or third degree AV-blockmay benefit from pre-treatment with pacemaker in orderto tolerate b-blockers, although this approach has,however, not been formally tested. Diabetes or inter-mittent lower limb claudication are not absolute con-traindications for b-blockers use.21;29 – 31

Drug interactions

b-blockers may show pharmacokinetic and pharmacody-namic interactions with other drugs.32 Aluminium salts,cholestyramine, and colestipol may decrease the ab-sorption of b-blockers. Alcohol, phenytoin, rifampicin,and phenobarbital, as well as smoking, induce hepaticbiotransformation enzymes and decrease plasma con-centrations and elimination half-lives of lipophilic b-blockers. Cimetidine and hydralazine may increase thebioavailability of propranolol and metoprolol by reducinghepatic blood flow. Caution should be exercised in pa-tients who are taking verapamil, diltiazem or variousantiarrhythmic agents, which may depress sinus-nodefunction or AV conduction. Additive effects on blood



6/22

pressure between b-blockers antagonists and other an-tihypertensive agents are often observed. Indomethacinand other non-steroidal antiinflammatory drugs antago-nize the antihypertensive effects of b-blockers.

Dosing of b-blockers

Appropriate dosing of b-blockers varies with the clinical

characteristics of the patient and the selected b-blocker.Table 2 shows the average daily oral doses in patientswith hypertension and angina. Table 3 indicates the av-erage recommended dose for intravenous use.

Clinical efficacy and use

The benefit and clinical indications of b-blockers havebeen clearly defined in many cardiovascular conditionsand agreement about their potential usefulness has beenclearly established in many clinical settings. b-Blockersare safe to use when contraindications have been ex-cluded and the appropriate dosage regimen is used.Abrupt discontinuation should be avoided if possible toprevent withdrawal effects. In case of doubt, specialistadvice is recommended.

The benefit of b-blocker treatment has been welldocumented in the following conditions:

Acute Myocardial Infarction (AMI)

During the acute phase of myocardial infarction, oralb-blockers are indicated in all patients without contrain-dications (class I, level of evidence A). Intravenousadministration should be considered in patients with is-chaemic pain resistant to opiates, recurrent ischaemia

and for the control of hypertension, tachycardia andarrhythmias (Table 4).33 – 35

b-blockers limit infarct size, reduce life-threateningarrhythmias, relieve pain and reduce mortality includingsudden cardiac death.36 – 43 Two large trials were partic-ularly relevant to guide the use of b-blockers during thefirst hours of AMI. In the First International Study of In-farct Survival (ISIS-1) trial40 patients within 12 h of evo-

lution were randomised to receive i.v. atenolol followedby oral administration for 7 days, or conventionaltreatment, revealing a significant reduction in mortalityat 7 days (3.7% vs. 4.6%; equivalent to 6 lives saved per1000 treated). The benefit was mainly due to a reductionin heart rupture and was evident by the end of day 1 andsustained at 1 month and 1 year. In the other large study,the Metoprolol in Myocardial Infarction (MIAMI),41 i.v.metoprolol followed by oral administration did not sig-nificantly reduce 15-day mortality as compared to pla-cebo (4.3–4.9% (ns)). A meta-analysis of 28 early trials ofi.v. b-blockers43 revealed an absolute reduction of short-term mortality from 4.3% to 3.7% (7 lives saved/1000patients treated). This significant albeit small benefitwas demonstrated before the reperfusion era. Similarfindings were reported in a more recent meta-analysisof 52 trials, most of them including a small number ofpatients.44

Two trials of randomised i.v. b-blockade were con-ducted after the widespread use of reperfusion therapyin AMI,45;46 but the number of events was too small toestablish clear conclusions. In the second Thrombolysis inMyocardial Infarction (TIMI-II) trial,45 thrombolysed pa-tients were randomly assigned to early i.v. and oralmetoprolol versus oral administration after day 6. Rein-farction and recurrent ischaemia were less frequent inthe early b-blocker group and when treatment was ad-

Table 3 Intravenous dosing of b-blockers

Drug Loading dose Maintenance dose

Atenolol 5 þ 5 mg Oral, 50–100 mg/dayEsmolol 0.5 mg/kg over 1–5 min 0.05–0.3 mg/kg/minLabetalol 20 mg in 2 min 2–10 mg/minMetoprolol 2.5–5 mg i.v. bolus over 2 min; up to three doses Oral, 25–100 mg/12 hPropranolol 0.15 mg/kg 0.10–0.20 mg/kg/min oral, 80–240 mg/day

Table 4 Use of b-blockers in AMI: guidelines

Setting/indication Class Level Ref.

i.v. administration

For relief of ischaemic pain I B 33, 34To control hypertension, sinus tachycardia I B 33Primary prevention of sudden cardiac death I B 35Sustained ventricular tachycardia I C 33Supraventricular tachyarrhythmias I C 33, 34To limit infarct size IIa A 33All patients without contraindications IIb A 33

Oral administration

All patients without contraindications I A 33, 34



7/22

ministered within 2 h of symptom onset, there was areduction of the composite endpoint of death or rein-farction. Data from the US National Registry of Myocar-dial Infarction 247 showed that immediate b-blockeradministration in patients with AMI treated with t-PAreduces the occurrence of intracranial haemorrhage,although this benefit is small (0.7% and 1.0%; 3 patients/1000 treated). However, a post-hoc analysis of the first

Global utilization of streptokinase and t-PA for occludedcoronary arteries (GUSTO-I) trial and a systematic reviewof the available experience do not support the routine,early, intravenous use of b-blockers,33;44;48 at least whenthrombolytic treatment or primary percutaneous inter-vention is performed. New data from the PAMI (PrimaryAngioplasty in AMI) Stent-PAMI, Air-PAMI and CADILLAC(Controlled Abciximab and Device Investigation to LowerLate Angioplasty Complications) trials seems to demon-strate a reduction in mortality when b-blockers are usedbefore primary percutaneous interventions.49 – 51

Secondary prevention after myocardialinfarction

Oral b-blockers are recommended for long-term use(indefinitely) in all patients who recover from AMI and donot present contraindications (class I, level of evidenceA) (Table 5).33 – 35;52 – 58 b-blockers are underused for thisindication.59 – 60

Several large, long-term trials involving more than35,000 survivors of myocardial infarction have demon-strated that the use of b-blockers in patients recoveringfrom an episode of AMI improves survival by 20–25%through a reduction of cardiac mortality, sudden cardiacdeath and reinfarction.43;44;49;61 – 66 Positive results have

been found in trials comparing propranolol, metoprolol,timolol, acebutolol and carvedilol with placebo; con-versely, no benefit was demonstrated in trials withalprenolol, atenolol, oxprenolol or xamoterol.44 A meta-analysis of 82 randomised trials (31 with long-term fol-low-up) provides strong evidence for the long-term useof b-blockers to reduce morbidity and mortality afteracute MI even if aspirin, fibrinolytics or angiotensinconverting enzyme inhibitors (ACE-I) were co-adminis-tered.44 An annual reduction of 1.2 deaths in 100 pa-tients treated with b-blockers after myocardialinfarction was observed; that is, about 84 patients willrequire treatment for 1 year to avoid one death.44 Sim-ilarly, the annual reduction for reinfarction was 0.9events in 100 treated patients; equivalent to the need to

treat 107 patients for 1 year to avoid one non-fatalreinfarction. In the retrospective analysis of the Coop-erative Cardiovascular Project, including over 200,000patients with myocardial infarction, b-blocker use wasassociated with a reduction in mortality, independent ofage, race, presence of pulmonary disease, diabetes,blood pressure, ejection fraction, heart rate, renalfunction and treatment received during hospitalisation

including myocardial revascularisation.21In the Beta-blocker Heart Attack Trial (BHAT)61 pa-

tients were randomised 5–21 days after AMI to receivepropranolol or placebo. Mortality after a mean follow-upof 2 years was reduced by 25% (7% vs. 9.5%) (25 livessaved/1000 treated). In the Norwegian trial,62 patientswere randomly assigned 7–28 days after AMI to receivetimolol or placebo; mortality was reduced from 9.8% to7.2%, (26 lives/1000 treated) over a follow-up of 25months. Sudden cardiac death and reinfarction were alsosignificantly reduced. Interestingly, the beneficial influ-ence of timolol on survival was sustained for at least 6years.63 In the study of Hjalmarson et al.,64 metoprololgiven first intravenously and then orally, mortality at 90days was reduced by 26%. In the Boissel et al. trial Ace-butolol et Prevention Secondarie de l’Infartus (APSI)trial,65 including high risk patients 2–22 days after AMI,there was also a significant 48% reduction in mortalityassociated with the b-blocker treatment. In the Carve-dilol Post Infarct Survival Control in Left VentricularDysfunction (CAPRICORN) trial including patients 2–21days after AMI with reduced left ventricular ejectionfraction and receiving ACE-I, all-cause mortality waslower in the carvedilol group than in the placebo group(12% vs. 15%).66 The significant mortality reductions inheart failure observed with b-blockers and the result ofthe CAPRICORN trial further support the use of these

agents in high risk patients with impaired ventricularfunction or failure after infarction and demonstrate thatthe benefit of b-blockers is observed also in patientsreceiving treatment according to current standards, in-cluding reperfusion therapy and ACE-I.

Although the benefit of b-blockers is observed in abroad population after infarction,21;30;67 the benefit oflong-term therapy is greatest in high-risk patients (i.e.,those with evidence of large or anterior infarction) andthere is continued debate about whether low-risk sub-jects (young, revascularised patients without previousinfarction, residual ischaemia or ventricular arrhyth-mias and normal ventricular function) should be trea-ted with b-blockers because their long-term prognosisis favourable. Chronic stable ischaemic heart disease

Table 5 Use of b-blockers in secondary prevention after infarction: guidelines


All patients without contraindications, indefinitely I A 33, 34, 52–57To improve survival I A 33, 52–53To prevent reinfarction I A 33, 52–53Primary prevention of sudden cardiac death I A 35To prevent/treat late ventricular arrhythmias IIa B 33, 35



8/22

patients and patients with atherosclerosis (carotidplaque) may benefit from a combined treatment withstatins and b-blockers.68 Treatment with b-blockers indiabetic patients seems to be more effective than innon-diabetics and the risk of complications is negligi-ble.69 Other subgroups at high risk, include late ven-tricular arrhythmias and post infarction ischaemia, Q wave and non-Q wave infarctions and elderly patients

also benefit from b-blockers.21;67 Although relativecontraindications once may have been thought to pre-clude the use of b-blockers in some patients, new ev-idence suggests that the benefits of b-blockers inreducing reinfarction and mortality may actually out-weigh its risks, even in patients with (1) insulin de-pendent diabetes mellitus; (2) chronic obstructivepulmonary disease; (3) severe peripheral vascular dis-ease; (4) PR interval up to 0.24 s; and (5) moderateleft ventricular failure.21 It is also emphasized that theuse of b-blockers in such patients requires carefulmonitoring of the patient to be certain that adverseevents do not occur.34

Non-ST-segment elevation acute coronarysyndromes

Patients with Acute Coronary Syndromes (ACS) withoutST-segment elevation should be treated with b-blockersas soon as possible, to control ischaemia and preventAMI/reinfarction (class I, level of evidence B).65 – 67 Afterthe acute phase, all patients should receive b-blockersduring long term for secondary prevention (class I, levelof evidence A) (Table 6).70;71

There are few randomised studies with b-blockers inpatients with unstable angina and non-Q wave myocar-dial infarction,73 – 75 and the new non-ST- segment ele-

vation ACS terminology makes the analysis of possibleeffect even more difficult. Henceforth, the recommen-dations are based on small studies in unstable angina aswell as in the evidence in acute ST-segment elevation

myocardial infarction and stable patients with ischaemiaand previous myocardial infarction. In fact, there arefew studies in patients with unstable angina comparingb-blockers with placebo A meta-analysis suggested thatb-blocker treatment was associated with a 13% relativereduction in risk of progression to AMI.76 Although nosignificant effect on mortality has been demonstrated inunstable angina in these relatively small trials, larger

randomised trials of b-blockers in patients with acute orrecent MI have shown a significant effect on mortal-ity.43;44 In addition, a retrospective analysis from theCooperative Cardiovascular Project21 indicates that therelative risk of death was lower in patients with non-Q wave myocardial infarction receiving b-blockers. Pooleddata from 2,894 patients with acute coronary syndromesincluded in five randomised, controlled trials of abcix-imab during coronary intervention showed a reductionof 30 day and 60 day mortality associated with the useof b-blockers.77 There is no evidence that any specificb-blocking agent is more effective in producing benefi-cial effects in unstable angina and oral therapy shouldbe aimed to achieving a target heart rate between 50and 60 beats per minute. The intravenous route shouldbe preferred in patients at high risk (class II, level ofevidence B).70;71 b-blockers can increase coronary arterytone and are contraindicated in vasospastic anginawithout obstructive lesions.78

Chronic, stable ischaemic heart disease

All patients with chronic, stable ischaemic heart diseaseshould receive long-term treatment with b-blockers tocontrol ischaemia, prevent infarction and improve sur-vival. This is considered as a class I recommendation,level of evidence A in patients with previous myocardial

infarction and class I, levels of evidence A, B and C (tocontrol ischaemia, prevent infarction and improve sur-vival, respectively) in the absence of a previous historyof infarction (Table 7).33;34;52;53;57;72;79 b-blockers should

Table 6 Use of b-blockers in non-ST-segment elevation ACS: guidelines


Early benefit, reduction of ischaemia I B 70–72Early benefit, prevention MI I B 70, 71Long-term secondary prevention I B 70, 71

Table 7 Use of b-blockers in chronic, stable ischaemic heart disease: guidelines


Previous infarction

To improve survival I A 33–35, 52, 53To reduce reinfarction I A 33, 72To prevent/control ischaemia I A 33–35, 52, 53

No previous infarction

To improve survival I C 33–35, 52, 53To reduce reinfarction I B 33, 79To prevent/control ischaemia I A 33, 52, 53



9/22

be considered as the first choice in patients with chronicangina or ischaemia, and hypertension, previous infarc-tion or poor ventricular function.53;57;58;79 They appear tobe underused for this indication.80

b-blockers are highly effective to control exercise-induced angina, improve exercise capacity,81 – 87 and toreduce or suppress both symptomatic and asymptomaticischaemic episodes.85;88 – 91 No clear clinical differences

have been demonstrated between different b-blockers.Also, no clinical relevant differences were found whencomparing b-blockers with calcium channel blockers forthe control of ischaemia.92 – 95 Combination therapy withnitrates and b-blockers may be more effective than ni-trates or b-blockers alone.96 b-blockers may also becombined with dihydropyridines,97 – 101 but the combina-tion with verapamil and diltiazem increases the risk ofbradycardia or AV block.

If possible, b-blockers (and other anti-ischaemicdrugs) should be withheld for four half-lives (usuallyabout 48 h) when a stress test is planned for the diagnosisand risk stratification of patients with suspected coro-nary artery disease.102 b-blockers should be withdrawngradually to avoid withdrawal effects.26;103

The effect on prognosis in patients with stable anginahas not been specifically studied in large trials, and mostof the information comes from studies in the pre-thrombolytic era, when myocardial revascularisation wasmore restricted. A history of angina has, however, beenpresent in about 1/3 of patients recruited in post in-farction studies with b-blockers. The b-blockers poolingproject67 reported a highly significant reduction in mor-tality in this subgroup, and it seems reasonable to assumethat b-blockers have the potential to prevent death, es-pecially sudden cardiac death, and myocardial infarctioneven when there has been no prior infarction.53;57;79

The effects of b-blockers in patients with stable an-gina without prior MI or hypertension have been inves-tigated in some randomised controlled trials. In the TotalIschaemic Burden European Trial (TIBET)104, no differ-ence was found between atenolol and nifedipine, and inthe Angina Prognosis Study in Stockholm (APSIS)105 theclinical outcome was similar in the groups treated withmetoprolol and verapamil. In the Atenolol Silent Is-chaemia Study (ASIST),91 in patients with mild angina,atenolol decreased ischaemic episodes at 6 weeks ascompared with placebo and after 1 year there was animprovement in the cardiovascular combined outcomes.

In the Total Ischaemic Burden Bisoprolol Study (TIBBS)106

bisoprolol was more effective than nifedipine in reducingthe number and duration of ischaemic episodes in pa-tients with stable angina. In the International Multicen-ter Angina Exercise (IMAGE) trial,107 metoprolol wasmore effective than nifedipine in controling exerciseinduced ischaemia.

Heart failure

All patients with stable, mild, moderate and severechronic heart failure from ischaemic or non-ischaemiccardiomyopathies and reduced left ventricular ejectionfraction, in NYHA class II–IV, should be treated withb-blockers, unless there is a contraindication (class I,level of evidence A).55;108 In patients with left ven-tricular systolic dysfunction, with or without symp-tomatic heart failure following an AMI, long-termb-blockade is recommended in addition to ACE inhibi-tion to reduce mortality (class I, level of evidenceA).55;108 Finally, b-blockers are also recommended inpatients with chronic heart failure and preserved leftventricular function (class IIa, level of evidence C) 108

(Table 8). b-blockers are underused in patients withheart failure.109

The evidence of clinical benefit on b-blockers in pa-tients with chronic heart failure with systolic left ven-tricular dysfunction was demonstrated in a number ofsmall studies and in several, large, prospective, rando-mised, placebo controlled trials, including a total of over15,000 patients.110 – 125 Placebo-controlled mortality tri-als with carvedilol,66;116;119;124;125 bisoprolol121 andmetoprolol122;123 have been associated with a long-termreduction in total mortality, cardiovascular mortality,sudden cardiac death and death due to progression of

heart failure in patients in functional class II–IV. In thesestudies, b-blocking therapy also reduced hospitalisations(all, cardiovascular and heart failure-related), improvedthe functional class and led to less worsening of heartfailure than placebo. This beneficial effect has beenconsistently observed in subgroups of different age,gender, functional class, left ventricular ejection frac-tion and ischaemic or non-ischaemic aetiology, diabeticsand non-diabetics. Black patients may be an exception,since in the BEST trial this ethnic group lacked the ben-efit from b-blocker therapy in heart failure.126 In smaller,controlled studies b-blockade has been shown to improve

Table 8 Use of b-blockers in chronic heart failure: guidelines


All stable patients, with symptomatic heart failure and reduced LVEF,functional class II–IV (to prolong survival)

I A 55, 108

LVSD without symptoms after AMI I A 55, 108LVSD without symptoms, no previous MI I B 55Chronic HF with preserved systolic function (to reduce heart rate) IIa C 108Acute, compensated heart failure after AMI IIa B 135Patient stable after acutely decompensated chronic heart failure I A 135

AMI: Acute Myocardial Infarction; LVEF: Left Ventricular Ejection Fraction; LVSD: Left Ventricular Systolic Dysfunction.



10/22

ventricular function.115 – 127 Exercise capacity may alsoimprove114 as well as symptoms and quality of life, 17 butthese effects usually are marginal and have not beenconsistently demonstrated in all trials comparingb-blockers with placebo.128

In the second Cardiac Insufficiency Bisoprolol Study(CIBIS-2)121 symptomatic patients in NYHA class III or IV,with left-ventricular ejection fraction of 35% or less,

receiving standard therapy with diuretics and ACE-in-hibitors, were randomly assigned to receive bisoprolol orplacebo during a mean follow of 1.3 years. The study wasstopped early because bisoprolol showed a significantmortality benefit (11.8% vs. 17.3%) (55 lives saved/1000treated; Number Needed to Treat (NNT) for 1.3 year tosave 1 life¼18). There were significantly fewer suddencardiac deaths among patients on bisoprolol than inthose on placebo (3.6% vs. 6.3%). Treatment effects wereindependent of the severity or cause of heart failure.

In the Metoprolol Randomised Intervention Trial(MERIT-HF)122 patients with chronic heart failure in NYHAfunctional class II–IV and ejection fraction 40% andstabilised with optimum standard therapy, were ran-domly assigned metoprolol CR/XL or placebo. This studywas also stopped early on the recommendation of theindependent safety committee after a mean follow-up of1 year. All-cause mortality was lower in the metoprololgroup than in the placebo group (7.2%, per patient-yearof follow-up vs. 11.0%) (38 lives saved/1000 treated;number needed to treat (NNT) for 1 year to save 1 life¼ 28). There was also a 41% reduction in sudden cardiacdeath and 49% reduction in deaths from worsening heartfailure.

In the Carvedilol Prospective Randomised CumulativeSurvival (COPERNICUS) study,124 patients who hadsymptoms of heart failure at rest or on minimal exertion,

clinically euvolemic, and with an ejection fraction of


11/22

practice and lists the contraindications. Detailed prac-tical guidance on the use of b-blockers in heart failurecan be found elsewhere.133

Heart failure and preserved systolic function

There is a paucity of data regarding the possible benefitof b-blockers in patients with heart failure and preservedsystolic left ventricular function. Accordingly, the rec-

ommended use of b-blockers in these patients is empir-ical, based mainly on the possible benefit of reducingheart rate and improving myocardial ischaemia.

Acute heart failure

There are no randomised clinical trials with b-blockersin acute heart failure targeted to improve the acutecondition. In the Gothenburg study i.v. metoprolol or

Table 9 Practical guidance on using b-adrenergic blockers in heart failure (modified from Ref. 133)

Who should receive b-blocker therapy

All patients with chronic, stable heart failure Without contraindications (symptomatic hypotension or bradicardia, asthma)

What to promise

Treatment is primarily prophylactic against death and new hospitalisations for cardiovascular reasons. Some patients willexperience improvement of symptoms.

When to start No physical evidence of fluid retention (use diuretics accordingly) Start ACE-I first if not contraindicated In stable patients, in the hospital or in outpatient clinics NYHA class IV/severe CHF patients should be referred for specialist advice Review treatment. Avoid verapamil, diltiazem, antiarrhythmics, non-steroidal anti-inflamatory drugs

Beta-blocker

Bisoprolol, carvedilol or metoprolol

Dose

Start with a low dose Increase dose slowly. Double dose at not less than 2 weekly intervals Aim for target dose (see above) or, if not tolerated, the highest tolerated dose

Starting dose mg Target dose mg

Bisoprolol 1.25 once daily 10 once dailyCarvedilol 3.125 twice daily 25–50 twice dailyMetoprolol CR/XL 12.5–25 once daily 200 once daily

Monitoring

Monitor for evidence of heart failure symptoms, fluid retention, hypotension and bradycardia Instruct patients to weigh themselves daily and to increase their diuretic dose if weight increases

Problem solving

Reduce/discontinue b-blocker only if other actions were ineffective to control symptoms/secondary effects Always consider the reintroduction and/or uptitration of the b-blocker when the patient becomes stable Seek specialist advice if in doubt.

Symptomatic hypotension (dizziness, light headedness and/or confusion)

Reconsider need for nitrates, calcium channel blockers and other vasodilators If no signs/symptoms of congestion consider reducing diuretic dose

Worsening symptoms/signs (increasing dyspnoea, fatigue, oedema, weight gain) Double dose of diuretic or/and ACE-I. Temporarily reduce the dose of b-blockers if increasing diuretic dose does not work Review patient in 1–2 weeks; if not improved seek specialist advice If serious deterioration halve dose of b-blocker Stop b-blocker (rarely necessary; seek specialist advice)

Bradycardia

ECG to exclude heart block Consider pacemaker support if severe bradycardia or AV block or sick sinus node early after starting b-blockers Review need, reduce or discontinue other heart rate slowing drugs, e.g., digoxin, amiodarone, diltiazem Reduce dose of b-blocker. Discontinuation rarely necessary

Severe decompensated heart failure, pulmonary oedema, shock

Admit patient to hospital Discontinue b-blocker if inotropic support is needed or symptomatic hypotension/bradycardia is observed

If inotropic support is needed, levosimendan may be preferredCHF: Congestive Heart Failure; NYHC: New York Heart Association.



12/22

placebo was initiated early after an AMI and followed byoral therapy for three months. Patients with newsymptoms of heart failure were less frequently found inthe metoprolol group, and in patients with signs ofpulmonary congestion with basal rales and/or i.v. furo-semide, metoprolol therapy reduced mortality andmorbidity.134 In the COPERNICUS trial, b-blocker therapystarted early after acute decompensation of chronic

heart failure was associated with a long-term reductionin mortality.124 In the CAPRICORN trial patients withheart failure or left ventricular dysfunction randomisedearly after AMI also received benefit from b-blockertherapy.66 As recommended in the ESC acute heartfailure guidelines.135 Patients with acute overt heartfailure including more than basal pulmonary rales,b-blockers should be used cautiously. In these patients,if ongoing ischaemia and tachycardia are present, in-travenous metoprolol can be considered. (class IIb, levelof evidence C). However, in patients with AMI whostabilise after acute heart failure, b-blockers should beinitiated early (class IIa, level of evidence B). In patientswith chronic heart failure b-blockers should be initiatedwhen the patient has stabilised after the acute episode(usually after 4 days) (class I, level of evidence A). Theoral initial dose of bisoprolol, carvedilol or metoprololshould be small and increased slowly and progressivelyto the target dose used in the large clinical trials. Up-titration should be adapted to individual response. Pa-tients on b-blockers admitted due to worsening heartfailure, should be continued on this therapy in generalunless inotropic support is needed but dose could bereduced if signs of excessive dosages are suspected (lowheart rate and hypotension).

Arrhythmias (Table 10)

Sinus tachycardia

Sinus tachycardia is not a primary disorder and treatmentshould be directed to the underlying cause. In selectedindividuals b-blockers can be used to slow heartrate136;137 (class I, level of evidence C) (e.g., if a fastheart rate produces symptoms) and are especially indi-

cated in situations of anxiety, after myocardial infarc-tion, in patients with heart failure, hyperthyroidism andhyperdynamic b-adrenergic state.137;138 In patients withpheochromocytoma, b-blockers are also effective tocontrol sinus tachycardia, but if given alone hypertensivecrisis can occur secondary to unopposed a-receptormediated constriction.139

Supraventricular tachycardias

b-blockers are effective for suppressing atrial prematurebeats and controlling heart rate and conversion of focalatrial tachycardia, as well as preventing its recurrence,in many instances the result of increased sympathetictone140 such as after surgery (class I, level of evidence C)(Table 10).137 On the contrary, multifocal atrial tachy-cardia is frequently associated with severe obstructivelung disease, in which case b-blockers are ineffective andcontraindicated. AV nodal reciprocating tachycardias,the most common form of paroxismal supraventriculartachycardia, also responds well to i.v. administration ofpropranolol, metoprolol, atenolol, sotalol or timolol,with a reduction in heart rate, conversion to sinusrhythm or facilitating the success of vagal manoeu-vres137;141 – 145 (class I, level of evidence C). b-blockers arealso useful for the prevention of recurrent episodes. Oral

Table 10 Use of b-blockers in arrhythmias: guidelines


Supraventricular arrhythmias

Sinus tachycardia I C 137Focal atrial tachycardia, for cardioversion IIa C 137Focal atrial tachycardia, for prevention of recurrence I B 137Atrioventricular nodal reciprocating tachycardia I C 137Focal junctional tachycardia IIa C 137Non-paroxysmal junctional tachycardia IIa C 137WPW with symptomatic arrhythmias IIa C 137

Atrial flutter

Rate control of atrial flutter, poorly tolerated IIa C 137Rate control of atrial flutter, well tolerated I C 137

Atrial fibrillation (ESC/AHA/ACC)

Prevention (post AMI, HF, HTA, post surgery, post conversion to sinus rhythm) I A 136Chronic control of heart rate I B 136Acute control of heart rate I A 136Conversion to sinus rhythm IIa B 136Combination with digoxin, for heart rate control IIa A 136Acute control of HR in heart failure IIb C 136

Ventricular arrhythmias

Control of arrythmias early after AMI (i.v.) I A 33Control of arrythmias late after AMI I A 33, 35, 52, 56, 57Prevention of sudden cardiac death in heart failure and after MI I A 137



13/22

administration of b-blockers is very effective to preventparoxysmal tachycardias precipitated by emotion or ex-ercise.146 Oral propranolol, atenolol, nadolol, and sotalolwere found to be effective in the long term prophylactictreatment of patients with paroxysmal supraventricu-lar tachycardias145 (class I, level of evidence C).137

b-blockers are also recommended for the treatment ofother forms of supraventricular tachycardias, including

focal junctional tachycardia and non-paroxysmal junc-tional tachycardia137 (Table 10).

Tachycardias in WPW syndrome

b-blockers may be effective in some patients with su-praventricular arrhythmias in the presence of WPW, ifthe accessory pathway is incapable of rapid anterogradeconduction as demonstrated in an electrophysiologicalstudies.137;145 However, b-blockers may cause very seri-ous adverse events. b-blockers, as well as digitalis andcalcium channel blockers, do not block the accessorypathway and may even enhance conduction, resulting ina very rapid ventricular response which may lead to se-

vere hypotension or cardiac arrest.136;147 – 149

For thisreasons, b-blockers are contraindicated in arrhythmiasassociated with WPW syndrome. b-blockers are alsocontraindicated in patients with sick sinus or bradycar-dia/tachycardia syndrome, as sinus arrest with syncopemay occur.145

Atrial flutter

b-blockers are not effective for conversion of atrialflutter to sinus rhythm but may be effective for ven-tricular rate control, for this reason they are indicated instable patients (class I, level of evidence C).137

Atrial fibrillationb-blockers may be effective to prevent episodes of AtrialFibrillation (AF), to control heart rate, to revert atrialfibrillation to sinus rhythm and to maintain sinus rhythmafter it is restored (Table 10).136

Prevention. The incidence of atrial fibrillation is lower inpatients receiving b-blockers. This effect has been ob-served in randomised studies in patients with heart fail-ure, during secondary prevention after acute myocardialinfarction, in hypertension and after elective non-car-diac surgery.136

Control of heart rate. Propranolol, atenolol, metoprolol,or esmolol may be given i.v. to acutely control the rateof ventricular response to AF in specific settings, espe-cially in states of high adrenergic tone (e.g., postoper-atively), but i.v. administration in heart failure is notrecommended. b-blockers have also proved to be ef-fective in patients with AF complicating thyrotoxicosis,AMI, chronic stable coronary artery disease150;151 andduring pregnancy.152 For acute control of heart rate, in-travenous esmolol is the recommended agent.136;153

For long-term use, b-blockade is a safe therapy tocontrol heart rate in AF patients and antagonises theeffects of increased sympathetic tone. In seven of 12

comparisons with placebo, b-blockers were effective incontrolling resting heart rate. The effect was drugspecific, with sotalol, nadolol and atenolol being themost efficacious.150 Atenolol provided better control ofexercise-induced tachycardia than digoxin alone.154

Combinations of several agents may often be requiredto achieve adequate rate control, but care should betaken to avoid excessive slowing. In general, the com-

bination of digoxin and b-blockers appears to be moreeffective than either digoxin or b-blocker alone andbetter than the combination of digoxin and calciumchannel blockers.155 – 158

Conversion to sinus rhythm. There are few randomisedstudies exploring the efficacy of b-blockers to revert AFto sinus rhythm or to maintain sinus rhythm. Onerandomised, open-label, crossover study showed thatatenolol was as effective as sotalol and better thanplacebo at suppressing episodes of AF, reducing theirduration and associated symptoms.150 In AF after non-cardiac surgery, intravenous esmolol produced a more

rapid conversion to sinus rhythm than did intravenousdiltiazem,151, but other antiarrhythmic drugs arepreferred for cardioversion of AF to sinus rhythm.136

b-blockers may also reduce subacute recurrences afterconversion to sinus rhythm,151 bisoprolol being as effec-tive as sotalol159 and carvedilol160 to maintain sinusrhythm after AF.

Ventricular arrhythmias

b-blockers are effective in the control of ventriculararrhythmias related to sympathetic activation, includ-ing stress-induced arrhythmias, AMI, perioperative andheart failure, including the prevention of sudden

cardiac death (class I, level of evidence A)33;35;52;56;57

(Table 10). Most b-blockers have proved effective toreduce the number of ventricular premature beats. Insustained ventricular tachycardia, b-blockers includingpropanolol, sotalol, metoprolol and oral atenolol havebeen effective to suppress the tachycardia, but theexperience is limited and there is a lack of controlledstudies. Success of b-blocker to treat VF is anec-dotal.161 On the contrary, b-blockers have proven to bevery efficacious to prevent arrhythmias leading to sud-den cardiac death in different conditions, includingacute and chronic myocardial ischaemia, heart failureand cardiomyopathies.

Prevention of sudden cardiac death

There is clear evidence demonstrating that the benefitderived from b-blocker treatment in part is the conse-quence of a reduction in sudden cardiac death (SCD).Accordingly, b-blockers are clearly indicated in the pri-mary and secondary prevention of SCD in differentclinical settings and guidelines have been estab-lished33;35;162;163 (Table 11). However, it should bestressed that for secondary prevention of sudden cardiacdeath and in particular in the presence of severe leftventricular dysfunction, the use of b-blockers does not



14/22

preclude the identification and appropriate treatment ofischaemia and the use of implantable defibrillators. 35;163

Acute myocardial infarction

The use of b-blockers in AMI has been already discussed.For the prevention of VF, i.v. b-blockers are indicated inpatients with ventricular arrythmias33 (class I, level ofevidence A) (Table 11). SCD secondary to VF is veryfrequent after an acute coronary occlusion.164 – 167

b-blockers increase the threshold for VF during acuteischaemia and a decrease in VF was demonstrated insome placebo controlled trials with metoprolol, atenololand propranolol very early after onset of symp-toms.39;168;169 In a randomised study including 735 pa-tients within 4 h after the onset of chest pain, treatedwith intravenous propranolol followed by oral adminis-

tration, VF occurred in two patients in the b-blockergroup and in 14 of the control group ( p < 0:06).39 Also,i.v. metoprolol in patients with AMI significantly reducedthe number of VF episodes.39 However, in other largestudies, including the ISIS-2 and MIAMI40;41 no significantdecrease in the incidence of VF was noted. Besides, inthe thrombolytic era, there is a lack of controlled studiesexploring the effect of early b-blocker administration onthe incidence of VF, and the benefit of early intravenousadministration of b-blockers to prevent VF is question-able in patients treated with reperfusion therapy.33

After acute myocardial infarction, the efficacy ofb-blockers is related to a reduction in all-cause mortalityand sudden cardiac death and their use is recommendedin all patients for the primary prevention of sudden car-diac death (class I, level of evidence A)33;35;163 (Table 11).A recent analysis of 31 b-blockers trials170 showed that 13trials reported data on reduction of SCD, which was re-duced from 51% to 43% in patients treated with b-blockersvs. the untreated group. In the CAPRICORN trial in post MIpatients with left ventricular dysfunction, there was atrend toward SCD reduction in the carvedilol group.66

Heart failure

Patients with a history of congestive heart failure 67 ordepressed left ventricular function171 show the greatest

benefit from b-blockers in mortality reduction, includingSCD and are indicated in all patients for the prevention ofSCD (Class I, level of evidence A)35 (Table 11). A consis-tent contribution to the improved outcome by thesedrugs is related to a substantial reduction (between 40%and 55%) in SCD rates.115;122;172 The recent introduction ofnew therapies, such as thrombolytics, ACE-Inhibitors,aldosterone receptor blockers as well as concomitantrevascularisation or aspirin does not appear to limit theindependent benefit on clinical outcome provided byb-blockers, as suggested by the evidence of risk reduc-tions between 30% and 50%.21

Dilated cardiomyopathy

There are no specific studies demonstrating the benefit ofb-blockers for the prevention of sudden cardiac death in

dilated cardiomyopathy, but the reduction in mortalitywas similar in patients with ischemic or non-ischaemicheart failure115; accordingly, b-blockers are recom-mended for the prevention of sudden cardiac death in thispopulation (class I, level of evidence B)35;163 (Table 11).

Hypertrophic cardiomyopathy

Sudden cardiac death secondary to ventricular arrhyth-mias is frequent in patients with hypertrophic cardio-myopathy, especially during exercise and in the presenceof left ventricular outflow obstruction.163 Thoughb-blockers may improve symptoms, the currently avail-able data do not support the routine use of b-blockersin the prevention of sudden cardiac death in thesepatients.21;35;173 – 176

Mitral valve prolapse

Mitral valve prolapse is usually benign; its link with SCDhas been suggested but never conclusively demon-strated.35 No prospective studies have ever been con-ducted with b-blockers or antiarrhythmic drugs in thiscondition. Accordingly, no data are available to defineprophylactic interventions that may reduce the risk ofSCD. However, b-blocking agents are generally consid-ered as first choice therapy in symptomatic patients.Yet, the routine or selective use of b-blockers to prevent

Table 11 Use of b-blockers in the prevention of sudden cardiac death: guidelines

Disease/setting Indication Class Level Ref.

AMI Primary prevention I A 33Post-MI Primary prevention, in presence of HF or LV

dysfunctionI A 35, 163

Post-MI Primary prevention, during and post-MI I A 35, 163Post-MI Resuscitated VT/VF, spontaneous sustained VT IIa C 33, 35, 163

Heart failure Primary or secondary prevention I A 35Dilated cardiomyopathy Primary or secondary prevention I B 35, 163Myocardial bridging Primary prevention IIa C 35Long QT syndrome Primary prevention – symptomatic I B 35Long QT syndrome Secondary prevention – b-blockers+ICD I C 35Long QT syndrome Primary prevention – asymptomatic IIa C 35Catecholaminergic VT Primary or secondary prevention IIa C 35RV cardiomyopathy Primary prevention IIb C 35Patients with implantable defibrillators Secondary prevention IIa C 35, 163

HF: Heart Failure; LV: Left Ventricle; MI: Myocardial Infarction; RV: Right Ventricle; VT: Ventricular Tachycardia; BP: Blood Pressure.



15/22

sudden cardiac death in patients with mitral valve pro-lapse is not recommended.35

Myocardial bridging

Although it is considered as a benign condition, patientswith myocardial bridging may present with ischaemia andin some cases ventricular arrhythmias and sudden cardiacdeath.177 Symptoms usually improve with b-blockers.178

This information is based on a limited number of smallobservational studies (class IIa, level of evidence C).35

Long QT syndrome (LQTS)

Prolongation of the QT interval not secondary to ischae-mia or drugs is associated with life-threatening ventric-ular arrhythmias, sometimes exercise or stressrelated.179;180 b-Blockers are usually considered indicatedbut there is a lack of prospective, placebo-controlledstudies. In the largest of the retrospective analyses,conducted in 233 LQTS patients, all symptomatic forsyncope or cardiac arrest, mortality 15 years after thefirst syncope was 9% for the patients treated by antiad-

renergic therapy (b-blockers and/or left cardiac sympa-thetic denervation) and close to 60% in the group nottreated or treated with miscellaneous therapies.181 Thesedata support the benefit of b-blockers, however, they donot provide total protection and especially for the pa-tients with a history of cardiac arrest the risk of SCD re-mains unacceptably high. In symptomatic patients the useof b-blockers is considered a class I with a level of evi-dence B, in asymptomatic patients a class IIa, level ofevidence C35 (Table 11).

Catecholaminergic polymorphic ventricular

tachycardia

This clinical entity is characterised by adrenergically in-duced polymorphic ventricular tachycardia in the ab-sence of structural cardiac abnormalities and a familialhistory of syncope and SCD occurs in approximately onethird of the cases.182;183 The arrhythmias are reproduc-ible during exercise stress test or during isoproterenolinfusion.183 At the present time b-blockers seem to bethe only therapy that may be effective.183 Retrospectiveanalysis of the few published cases, shows SCD in 10.5%and 48% of patients with and without b-blocker therapy,respectively.183 Although this finding is not conclusivegiven the lack of controlled studies, b-blockers are rec-ommended for the primary and secondary prevention ofSCD (class IIa, level of evidence C).35

SCD in the normal heart

Idiopathic VF occurs in up to 8% of victims of SCD.184

According to the UCARE European registry, prevention of

recurrence with antiarrhythmic agents and b-blockersfailed.185

The Brugada syndrome186 is an arrhythmogenic dis-order associated with high risk of SCD caused by rapidpolymorphic ventricular arrhythmias mainly occurring atrest or during sleep in individuals with a structurallynormal heart. The occurrence of cardiac arrest at 3 yearfollow-up may be as high as 30%. The disease is charac-

terised by transient right bundle branch block andST-segment elevation in leads V1–V3. The efficacy of b-blockers in this condition has not been investigated.Accordingly, b-blockers are not currently recommendedin this condition.35

Other situations

b-blockers are also indicated in patients with pacemakersand implantable defibrillators for secondary prevention(class IIb and IIa, respectively, level of evidence C).35

Hypertension

b-Blockers are indicated in the treatment of hyperten-sion (class I, level of evidence A)46;52;53 (Table 12). In-travenous b-blockers can be used to treat hypertensiveemergencies. Current guidelines strongly recommendreduction of blood pressure to different levels accordingto the risk profile (the higher the risk the lower the idealblood pressure)52;56 – 58;187 – 189, and in most patients theappropriate control requires the use of two or more an-tihypertensive medications. Although the primary ob-jective in hypertensive patients is the control of bloodpressure levels, pharmacological treatment should alsoreduce morbidity and mortality and the selection of aspecific drug should be based on the patient profile.58

Thus, b-blockers may be considered as the first choicetherapy, alone or in combination, in patients with pre-vious myocardial infarction, ischaemic heart disease,arrhythmias or heart failure, asymptomatic left ventric-ular dysfunction, diabetes or high risk of coronary dis-ease, based on the efficacy of these drugs on thesepatient populations (class I, level of evidenceA).52;56;57;188

In early studies, treatment of hypertension with b-blockers was associated with an improvement in long-term outcomes, including a reduction in mortality, 190 – 192

stroke193 – 195 and heart failure.193 In the Swedish Trial inOld Patients with hypertension (STOP-Hypertensiontrial),190 all cause mortality and sudden cardiac death

was lower in the b-blocker (metoprolol, pindolol oratenolol) than in the placebo group. In the MAPHYstudy192, comparing metoprolol with thiazide, bloodpressure reduction was similar in both groups, but

Table 12 Use of b-blockers in the treatment of hypertension: guidelines


To control BP I A 52, 56, 57After MI, in ischaemia, tachyarrythmias, heart failure I A 52, 57, 188

MI: Myocardial Infarction; BP: Blood Pressure.



16/22

mortality was lower in the metoprolol group. This benefitof b-blockers compared with diuretics was not observedin other studies. In the Medical Research Council (MRC)trial191 atenolol failed to reduce cardiovascular events ascompared to placebo or diuretics in hypertensive pa-tients without previous myocardial infarction, angina andheart failure. In the HAPPHY study,194 b-blockers(metoprolol, atenolol or propranolol) did not improve

the clinical outcome as compared with diuretics. In ameta-analysis193 b-blockers were effective in preventingstroke and heart failure when compared with placebo butnot with diuretics.

In more recent trials, b-blockers were equally effica-cious to reduce blood pressure and cardiovascular riskwhen compared with calcium channel blockers196 andACE-inhibitors.196 – 199 In a meta-analysis, including the UKProspective Diabetes Study (UKPDS) (atenolol vs. cap-topril), STOP-Hypertension-2 (diuretics or b-blockers vs.ACE-inhibitors vs. dihydropiridine calcium channelblockers), CAPP (diuretics or b-blockers vs. captopril)and NORDIL (thiazide or b-blocker vs. diltizem), ACE-in-hibitors offered a similar cardiovascular protection ascompared with diuretics or b-blockers and calciumchannel blockers provided an extra 13% reduction in therisk of stroke but the risk of infarction was 19% higherthan with b-blockers or diuretics.200

The Losartan Intervention For Endpoint reduction inhypertension (LIFE) study compared the angiotensin IIinhibitor losartan with atenolol in hypertensive patientswith left ventricular hypertrophy but without myocardialinfarction or stroke within the previous 6 months, anginapectoris requiring treatment with b-blockers and heartfailure or left ventricular ejection fraction of 6 40%.Losartan was associated with a greater reduction instroke as compared atenolol (5% vs. 6.7%) over a mean

follow up of 8.4 years. Mortality and myocardial infarc-tion was similar in both groups.201

Aortic dissection

b-blockers are indicated to lower blood pressure in pa-tients with suspected or diagnosed aortic dissection(class I, level of evidence C) (Table 13).202

b-blockers reduce blood pressure and pulse pressure(systolic/diastolic pressure difference), which reflect the

force in the aortic wall. For this purpose b-blockers areconsidered the drug of choice in patients with aorticdissection although this therapeutic approach has notbeen tested in randomised clinical trials. Intravenousb-blockers (propranolol, metoprolol, atenolol, labetaloland esmolol) should be preferred to achieve rapid con-trol of blood pressure and can be used under carefulcontrol of blood pressure, heart rate and end-organ

perfusion. The recommended doses are indicated in Ta-ble 3 but have to be individually adjusted according tothe obtained response.193;194;203 While b-blocking agentsare usually adequate in most patients, combination withintravenous sodium nitroprusside may be required forsevere hypertension.

Hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy is a complex disease with abroad spectrum of manifestations and risk profile. Al-though b-blockers, including propranolol, atenolol,metoprolol, sotalol or nadolol have been successfully

used to relieve symptoms, improve physical capacity,control heart rate, treat arrhythmias, treat heart failureand prevent sudden cardiac death in patients with andwithout evidence of left ventricular outflow obstruction,their use has not been clearly standardised.176 Also,there is no proof that prophylactic drug therapy inasymptomatic patients to prevent or delay progression ofcongestive symptoms and improve prognosis.

Prophylactic use in non-cardiac surgery

b-Blockers are indicated in high cardiac risk patients,with present or past history of ischaemia, arrhythmias or

hypertension controlled by b-blockers and in patientswith ischaemia in perioperative testing submitted toelective non-cardiac surgery (specially vascular surgery),to prevent ischaemic events and arrhythmias (class I,level of evidence A). Also, b-blockers are indicated forthe treatment of perioperative hypertension, ischaemiaand arrhythmias identified preoperatively and previouslyuntreated (class IIa, level of evidence (B) (Table 14).54

Perioperative b-blocker therapy in high risk patients isunderutilized.205

In several studies, the preoperative administration ofb-blockers was associated with better control of bloodpressure206;207 and a reduction in perioperative ischae-

mia204;206 – 212

and arrhythmias.213;214

There is also evi-dence that patients with high risk for coronary heartdisease have a better outcome if treated with b-blockers

Table 13 Use of b-blockers in aortic dissection: guidelines


To lower blood pressure I C 202

Table 14 Use of b-blockers in non-cardiac surgery: guidelines


High cardiac risk (history of ischaemia, arrhythmias, hypertension, or stress inducedischaemia, to reduce ischaemic events and arrhythmias

I A 54

Preoperative use to control ischaemia, hypertension, arrhythmias I A 54Treatment of peroperative ischaemia, hypertension and arrhythmias IIa B 54



17/22

during hospitalisation for non-cardiac surgery, includinga reduction in mortality and cardiovascular complica-tions during and up to 2 years after surgery.215;216 In onesmall study, including 112 selected patients with riskfactors for ischaemic heart disease and a positive dobu-tamine stress test, bisoprolol was compared with placeboadministered before vascular surgery.216 Cardiac mor-tality (3.4% vs. 17%) and non-fatal infarction (0% vs. 17%)

were lower in the bisoprolol group. Boersma et al.217reanalysed the cohort of 1351 consecutive patients en-rolled in this study. Patients receiving b-blockers had alower risk of cardiac complications than those not re-ceiving b-blockers. In another trial215;218 atenolol givenbefore general surgery reduced the episodes of ischae-mia during ECG monitoring and improved the outcome atsix months follow-up as compared to placebo. Althoughthese studies were small and do not provide definiteanswers, the results suggest an improvement in out-come, especially in high-risk patients.

Vasovagal syncope

In vasovagal syncope b-blockers have been thought tolessen the degree of mechanoreceptor activation asso-ciated with an abrupt fall in venous return and block theeffects of elevated circulating adrenaline, but this effectcould not be demonstrated in five long-term follow-upcontrolled clinical studies219 – 223 and contradictory resultshave been reported in short term controlled clinicalstudies.224;225 A rationale for use of b-blockers is lackingin other forms of neurally mediated syncope and theymay be detrimental in dysautonomic syndromes.b-Blockers may enhance bradycardia in the carotid sinussyndrome and in all other cardio-inhibitory forms of ne-urally-mediated syncope. Therefore, at the moment

there is no evidence to support the use of b-blocker invasovagal syncope (level of evidence A).226

b-blockers during pregnancy

b-blockers have been used during pregnancy withoutevidence of teratogenic effects. Although there is lim-ited experience, b-blockers are considered as indicatedin pregnant women with hypertension, mitral stenosiswith pulmonary hypertension, coartaction of the aorta,ischaemic heart disease, supraventricular and ventricu-lar arrhythmias, and can be continued during deliv-ery.152;227;228 Selective agents, without effect on uterinecontraction are preferred.

References

1. Cruickshank JM, Prichard BNC. Beta-adrenoceptors. In: Cruickshank

JM, Prichard BNC, editors. Beta-blockers in clinical practice.

London: Churchill Livingstone; 1996. p. 9–86.

2. Tamargo JL, Delpon E. Optimisation of b-blockers pharmacology.

J Cardiovasc Pharmacol 1990;16(Suppl. 5):S8–S10.

3. Frishman WH, Lazar EJ, Gorodokin G. Pharmacokinetic optimisation

of therapy with beta-adrenergic-blocking agents. Clin Pharmacoki-

net 1991;20:311–8.

4. Frishman WH. Carvedilol. N Engl J Med 1998;339:1759–65.

5. Benfield P, Sorkin EM. Esmolol. A preliminary review of its pharma-

codynamic and pharmacokinetic properties and therapeutic effi-

cacy. Drugs 1987;33:392–412.6. Bristow MR. Pathophysiologic and pharmacologic rationale for

clinical management of chronic hart failure with beta-blocking

agents. Am J Cardiol 1993;71:12C–22C.

7. Bouzamondo A, Hulot JS, Sanchez P et al. Beta-blocker treatment inheart failure. Fundam Clin Pharmacol 2001;15:95–109.

8. Waagstein F. Beta-blockers in congestive heart failure: the evolution

of a new treatment concept-mechanism of action and clinical

implications. J Clin Basic Cardiol 2002;5:215–23.9. Man in’t Veld AJ, van der Meiracker A, Schalekamp MA. The effect

of beta-adrenoceptor antagonists on total peripheral resistance.

J Cardiovasc Pharmacol 1986;8(Suppl. 4):S49–60.

10. Frishman WH. Multifactorial actions of beta-adrenergic-blocking

drugs in ischemic heart disease: current concepts. Circulation

1983;67(Suppl. I):I-11-8.

11. Opie LH. Effect of beta-adrenergic blockade on biochemical and

metabolic response to exercise. Am J Cardiol 1985;55:95D.

12. Kukin ML, Kalman J, Charney R et al. Prospective, randomized

comparison of effect of long-term treatment with metoprolol or

carvedilol on symptoms, exercise, ejection fraction, and oxidative

stress in heart failure. Circulation 1999;102:2646–51.

13. Cleland JG, Dargie HJ. Arrhythmias, catecholamines and electro-

lytes. Am J Coll Cardiol 1988;62:55–9.

14. Shizukuda Y, Buttrick PM, Geenen D et al. Beta-adrenergic stimu-

lation causes cardiocyte apoptosis: influence of tachycardia andhypertrophy. Am J Physiol 1998;275:961–8.

15. Lowes BD, Gilbert EM, Abraham WT et al. Myocardial gene expres-sion in dilated cardiomyopathy treated with beta-blocking agents. N

Engl J Med 2002;346:1357–65.

16. Hjalmarson A, Elmfeldt D, Herlitz J et al. Effect on mortality of

metoprolol in acute myocardial infarction. A double-blind rando-mised trial. Lancet 1981;ii:823–87.

17. Hjalmarson A, Goldstein S, Fagerberg B et al. for the MERIT-HF Study

Group: Effects of controlled-release metoprolol on total mortality,

hospitalizations, and well-being in patients with heart failure. The

metoprolol CR/Xl randomized intervention trial in congestive heart

failure (MERIT-HF). JAMA 2000;283:1293–302.

18. Thadani U, Whitsett TL. Beta-adrenergic-blockers and intermit-

tent claudication: time for reappraisal. Arch Int Med 1991;151:

1705–7.

19. Radack K, Deck C. b-Adrenergic blocker therapy does not worsen

intermitent claudication in subjects with peripheral arterial disease.A meta-analysis of randomized controlled trials. Arch Int Med

1991;151:1769–76.

20. Kjekshus J, Gilpin E, Gali G et al. Diabetic patients and beta blockers

after acute myocardial infarction. Eur Heart J 1990;11:43–50.

21. Gottlieb S, McCarter R, Vogel R. Effect of beta-blockade on

mortality among high risk patients after myocardial infarction. N

Engl J Med 1998;338:489–97.

22. Poole-Wilson P. COMET study. European Congress of Cardiology.

Vienna, September 2003.

23. Chen J, Radford MJ, Wang Y et al. Effectiveness of beta-blocker

therapy after acute myocardial infarction in elderly patients withchronic obstructive pulmonary disease or asthma. J Am Coll Cardiol

2001;37:1950–6.

24. Salem S, McDevitt D. Central effects of beta-adrenoceptor antago-

nists. Clin Pharmacol Ther 1983;33:52–7.

25. Houston MC, Hodge R. Beta-adrenergic blocker withdrawal syn-dromes in hypertension and other cardiovascular diseases. Am Heart

J 1988;116:515–23.

26. Psaty BM, Koepsell TD, Wagner EH et al. The relative risk of incident

coronary heart disease associated with recently stopping the use of

beta-blockers. JAMA 1990;263:1653–7.

27. Salpeter SR, Ormiston TM, Salpeter EE et al. Cardioselective beta-

blockers for chronic obstructive pulmonary disease: a meta-analysis.

Respir Med 2003;97:1094–101.

28. Andrus MR, Holloway KP, Clark DB. Use of beta-blockers in patients

with COPD. Ann Pharmacother 2004;38:142–5.

29. Heintzen MP, Strauer BE. Peripheral vascular effects of beta-

blockers. Eur Heart J 1994;15:2–7.

30. Gheorghiade M, Goldstein S. Blockers in the post-myocardial infarc-

tion patient. Circulation 2002;106:394–8.



18/22

31. Haas SJ, Vos T, Gilbert RE et al. Are beta-blockers as efficacious in

patients with diabetes mellitus as in patients without diabetes

mellitus who have chronic heart failure? A meta-analysis of large-scale clinical trials. Am Heart J 2003;146:848–53.

32. Blaufarb I, Pfeifer TM, Frishman WH. Beta-blockers: drug interac-

tions of clinical significance. Drug Safety 1995;13:359–70.

33. Van de Werf et al, for the task force of the management of acutemyocardial infarction of the European Society of Cardiology.

Management of acute myocardial infarction in patients presenting

with ST-segment elevation. Eur Heart J 2003;24:28–66.

34. Report of the American College of Cardiology/American HeartAssociation Task Force on Practice Guidelines (Committee on

Management of Acute Myocardial Infarction) ACC/AHA. Guidelines

for the management of patients with acute myocardial infarction

American College of Cardiology. Available from: www.acc.org

September 1999.

35. Priori SG, Aliot E, Blomstr€om-Lundqvist C et al. for the Task Force on

Sudden Cardiac Death of the European Society of Cardiology. Eur

Heart J 2001;22:1374–450.

36. Waagstein F, HjalmarsonAC, Wasir HS. Apex cardiogram and systolic

time intervals in acute myocardial infarction and effect of practolol.Br Heart J 1974:1109–21.

37. Hjalmarson A, Elmfeldt D, Herlitz J et al. Effect on mortality of

metoprolol in acute myocardial infarction. A double-blind rando-

mised trial. Lancet 1981;ii:823–7.

38. Richterova A, Herlitz J, Holmberg S et al. The G€oteborg Metoprolol

Trial in Acute Myocardial Infarction. Effects on chest pain. Am JCardiol 1984;53:32D-6.

39. Norris RM, Brown MA, Clarke ED et al. Prevention of ventricularfibrillation during acute myocardial infarction by intravenous pro-

pranolol. Lancet 1984;2:883–6.

40. ISIS-1 (First International Study of Infarct Survival) collaborative

group. Randomised trialof intravenous atenolol among 16027 cases ofsuspected acute myocardial infarction: ISIS-1. Lancet 1986;II:57–66.

41. The MIAMI Trial Research Group: Metoprolol in acute myocardial

infarct